The SCCOR application focuses on the principal form of innate defense in mammalian airways, i.e., the mechanical system known as mucus clearance (MC). Our overarching hypothesis is that the efficiency of the MC system depends on the hydration of airway surfaces;failure to hydrate these surfaces produces mucus adhesion, inflammation, and infection of interluminal mucus that contribute to the pathogenesis of airways disease in cystic fibrosis and COPD. The SCCOR proposes six Projects to test this hypothesis: Project I: The Mucus Transport Apparatus: Why Two Layers? (J. Sheehan) will redefine the structure and function of the periciliary environment and the mucus layer;Project II: ASL volume and innate defense in CF and COPD Airways (R. Tarran), will investigate ASL homeostasis in normal and disease states;Project III: Dysregulated Airway Physiology in Scnnlb Transgenic Mice (S. Randell) focuses on key steps in COPD/CF pathogenesis in a unique mouse model of ASL volume depletion;Project IV: Smoking and airway innate host defense: in vivo studies (D. Peden) will provide critical baseline data on mucus properties and the response of the normal and cigarette smoke-exposed lung to mimics of aspects of COPD/CF disease;Project V: Mucus Dehydration and Evolution of COPD Lung Disease (R. Boucher) tests the hypothesis that relative dehydration of mucus is central to the initiation of COPD under basal and exacerbating conditions;and Project VI: Mucus Dehydration and Evolution of CF Lung Disease (S. Donaldson) also tests the hypotheses that mucus dehydration initiates disease progression in CF and hypertonic saline will be therapeutic. The Projects are supported by five Cores: Core A, Administrative and Biostatistics Core (R. Boucher);Core B, Sample Acquisition, Analysis, and Repository Core (N. Alexis);Core C, Mucus Analysis Core (J. Sheehan);Core D, Diagnostic Molecular Microbiology Core (M. Wolfgang);and Core E, Mucociliary and Cough Clearance by Gamma Scintigraphy Core (W. Bennett). This is a highly interactive SCCOR Program that will test the hypothesis that MC is the central innate defense mechanism of the airways and fails in major diseases (COPD, CF). The concepts that will emerge from this SCCOR will all spur development of novel therapies (referenced to hypertonic saline) that will transform the treatment of these major human diseases.